Neuroprotective Role of PGC-1α Against Oxidative Stress and Mitochondrial Dysfunction in Chronic Pain Pathophysiology: A Review

1. Introduction

Pain encompasses a distressing neurosensory and psychological state characterized by established or possible tissue impairment [1]. Previous studies have shown that clinical control of severe chronic pain has relied on mu-opioid receptor agonists such as morphine [2]. However, extended opioid therapy is associated with hyperalgesia, addiction liability, and lethal respiratory hypoventilation, which poses risks to many patients [3]. These therapeutic setbacks have encouraged researchers to investigate alternative opioid strategies, including preclinical testing of delta and kappa receptor agonists [4,5]. However, studies have demonstrated some shortcomings related to kappa- and delta-opioid receptors [6,7]. For example, kappa receptor agonists have been limited by dysphoric and psychotomimetic effects, whereas certain delta-opioid receptor agonists are known to provoke convulsant behavior [6,7]. Thus, the development of non-opioid therapeutic alternatives for chronic pain management remains essential [8].

Non-opioid adjuncts, notably gabapentinoids, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors, offer alternative options to overcome the limitations of conventional opioids [8]. However, these options remain suboptimal and are limited by adverse effects [9,10]. Specifically, duloxetine carries a risk of cardiovascular adverse events, whereas gabapentinoids can cause fatigue, ataxia, and have misuse potential [9,10]. Furthermore, minocycline, which has been explored for managing neuroinflammatory responses in persistent lower back pain by inhibiting glial activation, can cause tooth discoloration with prolonged use [11,12].

Chronic pain arises from peripheral and central sensitization, abnormal ion channel and neurotransmitter signaling, glial activation, and neuroimmune remodeling that modifies synaptic function [13,14]. Recent evidence suggests that management of chronic pain could target mitochondrial dysfunction and neuroimmune responses [13,15]. Persistent oxidative damage and disruption of cellular bioenergetics are hallmark features of chronic mitochondrial dysfunction, thereby contributing to neuronal hyperexcitability as well as central pain sensitization [15]. Many currently available analgesics relieve pain by attenuating nociceptive signaling [16]. However, they do not address the underlying mitochondrial and redox abnormalities implicated in chronic pain. At high doses or extended use, analgesics such as non-steroidal anti-inflammatory agents and opioids tend to impair mitochondrial function and increase oxidative damage [2,17,18]. Given the central role of mitochondrial dysfunction and oxidative stress in chronic pain, there is a growing need to identify upstream regulators of mitochondrial biogenesis as potential therapeutic targets. However, a major research gap remains, as standard analgesics are limited in their ability to restore these upstream pathways in chronic pain [19].

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) orchestrates mitochondrial generation and antioxidant pathways that modulate redox and inflammatory signaling in persistent pain conditions [20,21]. PGC-1α also regulates neuronal excitability and glial activation during nerve-injury-induced pain [22,23,24]. However, despite growing evidence implicating PGC-1α in various pain-related mitochondrial dysfunctions, its therapeutic exploration as a non-opioid target has not been documented for translational potential. This review synthesizes information from the recent literature on how PGC-1α modulates mitochondrial dysfunction and cellular oxidative damage in neuropathic, musculoskeletal, cancer-related, and opioid-induced hyperalgesia models [21,25,26]. It highlights the biological functions of PGC-1α and its impairment in the pathogenesis of persistent nociception [24]. It also explores targeting this coactivator using natural compounds and novel small-molecule activators or stabilizers as therapeutic approaches aimed at restoring mitochondrial integrity and mitigating oxidative burden [27,28]. This evidence positions PGC-1α as a promising druggable regulator of mitochondrial and redox homeostasis in chronic pain, with considerable potential to drive the development of mechanism-based, non-opioid analgesics. It also highlights the translational gaps that need to be addressed for clinical applications.

2. How Mitochondrial Dysfunction and Oxidative Stress Drive Chronic Pain

Chronic pain arises from complex cellular and molecular alterations within both central and peripheral neuronal networks [29]. Neuronal mitochondrial dysfunction reduces cellular respiration and increases reactive oxygen species (ROS) production [30]. This eventually contributes to sensory hyperexcitability and neuroinflammation [30]. Oxidative stress intensifies peripheral nociceptor sensitization and glial activation that sustain pain chronification [29]. ROS also disrupt ion channels, disturb inhibitory synaptic transmission, and alter monoaminergic signaling [31,32].

Within peripheral tissues, mitochondrial bioenergetic failure and oxidative stress activate sensory nerves and increase nociceptive signaling [33]. In the CNS, mitochondrial dysfunction also contributes to central sensitization and neuroinflammation [34,35]. Bioenergetic deficits within the spinal dorsal horn disrupt glutamate and calcium homeostasis, promoting excitotoxic nociceptive transmission [36,37]. Mitochondrial oxidative stress disrupts blood-brain barrier integrity by altering junctional protein complexes and increasing permeability, which facilitates neuroinflammation and contributes to central sensitization in persistent pain [35,38,39,40]. A reduction of PGC-1α expression correlates with mitochondrial ROS generation within chronic pain in experimental models [19,21,41]. Figure 1 illustrates the cellular mechanisms by which altered PGC-1α signaling contributes to mitochondrial dysfunction and persistent pain.

3. Induction of Mitochondrial Toxicity by Analgesics and Adjuvants

Some commonly used analgesics and adjuvants increase mitochondrial injury and ROS production, further reinforcing the need for mitochondria-targeted interventions [42,43,44]. For instance, NSAIDs such as diclofenac and indomethacin disrupt mitochondrial membrane potential and induce bioenergetic stress [45,46,47]. These mechanisms additionally elicit mitochondrial permeability and oxidative stress, which may culminate in apoptotic degradation [48,49]. In addition, indomethacin impairs PGC-1α signaling and triggers mitochondrial dysfunction within gastric cancer cells [50].

Chronic morphine exposure causes mitochondrial dysfunction, ROS accumulation, and morphine tolerance [51,52]. Opioids also increase mitochondrial DNA (mtDNA) release in immune cells to promote NF-κB activation [53,54,55]. Fentanyl and methadone disrupt mitochondrial morphology and reduce neuronal viability in neuronal models [56]. Consistently, PGC-1α prevents opioid-driven mitochondrial impairment [26].

Ketamine as an adjuvant for refractory neuropathic and cancer-related pain disrupts mitochondrial homeostasis in human-derived neurons by depleting ATP and compromising mitochondrial integrity [57,58,59]. These mitochondrial abnormalities may be associated with decreased hippocampal PGC-1α protein expression in neurobehavioral deficits [60]. Similarly, impairment of mitochondrial function could play a role in the side effects associated with adjunctive antidepressants prescribed for chronic pain [61]. Fluoxetine, for instance, downregulates mitochondrial ATP-production pathways in prefrontal cortex interneurons, suggesting an alteration in cellular bioenergetics [62]. Figure 2 summarizes the mitochondrial toxicity associated with commonly used analgesics and adjuvants.

4. Regulatory Signaling and Biological Functions of PGC-1α in Chronic Pain

PGC-1α is a central co-activator of transcription that governs mitochondrial formation, oxidative processes, and neuroinflammation [63]. It responds to epigenetic changes by recruiting histone acetyltransferases and the mediator complex to transcriptional complexes [64]. PGC-1α is highly enriched in tissues with elevated energy demands, specifically cardiac muscle, skeletal fibers, and brown adipose tissue [63]. In the CNS, PGC-1α supports neuronal resilience by promoting oxidative phosphorylation and endogenous antioxidant defenses [63]. Studies link disrupted PGC-1α pathway activity in neurodegenerative disorders and persistent pain conditions [23,65]. This evidence suggests that PGC-1α may help maintain protective metabolic plasticity in nociceptive circuits [41,66]. Impaired regulation of PGC-1α contributes to both neuropathic pain and neuroinflammation [67,68].

PGC-1α function is controlled via AMP-activated protein kinase (AMPK) alongside SIRT1 as energy-sensing pathways [63,69]. When cells experience sudden energy deficits such as during fasting, physical exertion, or oxygen deprivation, AMPK phosphorylates PGC-1α [63,70]. This phosphorylation event primes PGC-1α for subsequent deacetylation and activation by SIRT1 [63,69,70]. These modifications stimulate PGC-1α, promoting its transcriptional coactivation in the nucleus and establishing the AMPK/SIRT1/PGC-1α pathway as a core regulator of cellular energy balance [63,69,70].

Following post-translational activation, PGC-1α engages nuclear respiratory factors (NRF-1/NRF-2) to drive the expression of mitochondrial transcription factor A (TFAM) [63,70]. TFAM then enters the mitochondrial matrix, where it regulates mtDNA transcription and maintains oxidative phosphorylation [63,70]. PGC-1α also interacts with PPARs and estrogen-related receptors (ERRs) to regulate respiratory chain assembly alongside fatty acid oxidation pathways [20]. This cascade helps replace damaged mitochondria in neural tissue, protects cellular metabolism, and maintains mitochondrial energy demand [20]. This suggests that PGC-1α supports synaptic function in response to stress and persistent nociception [66,71].

Furthermore, PGC-1α drives CNS defenses against oxidative stress by upregulating catalase, superoxide dismutase 2, and glutathione peroxidase 1, thereby restricting ROS accumulation [63,72]. It also attenuates neuroinflammatory responses in astrocytes and microglia by suppressing the NF-κB axis and diminishing key cytokines [72]. In CNS models, PGC-1α preserves neuronal survival by limiting oxidative stress and inflammation, while its downregulation promotes neuronal damage [66]. The regulatory signaling pathways and protective biological functions of PGC-1α in chronic pain are summarized in Figure 3.

5. Experimental Evidence for PGC-1α in Chronic Pain

Experimental studies using rodent pain models, cultured cells, and human tissue samples indicate that PGC-1α promotes mitochondrial biogenesis alongside cellular redox balance and neuroimmune homeostasis in chronic pain [70,73,74,75]. Conversely, PGC-1α downregulation triggers mitochondrial dysfunction, increased ROS, glial activation, and pain chronification [70,74]. Restoration of PGC-1α signaling reverses mitochondrial quality control deficits while mitigating nociceptive behaviors [74,76,77]. However, PGC-1α pain-modulating mechanisms vary across chronic pain conditions, depending on tissue, cell type, and pathology. For example, PGC-1α limits cortical hyperexcitability [78], preserves cartilage integrity [79,80], and prevents muscle wasting in osteoarthritis [79]. In peripheral nerve injury, PGC-1α supports mitochondrial resilience in spinal sensory neurons and regulates microglial polarization [21,75]. In chemotherapy and diabetic-induced neuropathic pain, PGC-1α protects neural and peripheral nerves against mitochondrial dysfunction and oxidative injury [80,81,82,83,84]. PGC-1α reduces neuroinflammation and microglial polarization, while preserving GABAergic interneurons in cancer bone pain, [85,86]. In fibromyalgia, PGC-1α restores mitochondrial redox balance in muscle and hippocampal tissues [87,88], while in chronic headaches, it protects mitochondrial function and reduces trigeminal neuroinflammation [73,89,90]. Similarly, PGC-1α agonists counteract opioid-induced mitochondrial dysfunction and spinal apoptosis [26,91]. Thus, restoration of PGC-1α signaling could alleviate chronic pain through tissue- and mechanism-specific biological effects. Given that these biological effects vary across different pain conditions, evidence for PGC-1α in chronic pain subtypes is synthesized in the following sections.

5.1. Musculoskeletal Pain

Ageing-associated pain chronification reflects both peripheral tissue degeneration and altered pain processing within the primary somatosensory cortex [78]. Reduced PGC-1α in the cortex leads to insufficient control of excitatory neuronal signaling [78]. Research by Wu et al. (2024) showed that wild-type adult mice recovered from nerve-injury-induced mechanical and thermal hypersensitivity, whereas PGC-1α+/- mice failed to resolve these nociceptive behaviors [78]. Both genotypes showed increased calcium activity at day 7 post-injury, but persistent hyperactivation was observed only in PGC-1α+/- haploinsufficient mice [78]. In the cortex, reduced PGC-1α is associated with persistent hyperactivity and pain chronification, while in peripheral pain models, downregulation of PGC-1α directly influences mitochondrial dysfunction [67,78]. Such findings demonstrate PGC-1α supports pain resolution by maintaining mitochondrial homeostasis and limiting oxidative stress across central as well as peripheral pathways [67,78].

Osteoarthritis pain, characterized by joint damage involves spinal mitochondrial dysfunction and central sensitization [92]. Earlier work from Sun et al. (2022) indicated that upregulating spinal Sestrin2 (Sesn2) alleviates chronic pain via induction of AMPK/PGC-1α signaling to stimulate mitochondrial generation in spinal neurons [92]. Zhao et al. (2025) showcased that stromal cell-derived factor 1 (SDF-1) relieved osteoarthritis by activating PGC-1α in chondrocytes [93]. Consistently, Li and his colleagues (2024) showed that prenatal prednisone exposure (PPE) programs long-term osteoarthritis susceptibility in female offspring by suppressing PGC-1α in fetal cartilage [79]. PPE induced PGC-1α promoter hypermethylation, impaired mitochondrial biogenesis and glutamine metabolism, leading to chondrodysplasia [79]. Interestingly, restoration of PGC-1α expression via lentiviral transduction or ZLN005 reversed these mitochondrial defects and rescued cartilage matrix synthesis in osteoarthritis [79].

Post-traumatic osteoarthritis is accompanied by quadriceps wasting, which worsens joint instability and accelerates cartilage breakdown. A previous study demonstrated joint distraction paired with treadmill exercise reduced inflammatory responses within the joint space, protected cartilage, thereby delaying post-traumatic osteoarthritis development [75]. A combined human and rabbit study by Liu et al. (2024) found that lower skeletal muscle PGC-1α levels were associated with more severe osteoarthritis [75]. The quadriceps biopsies from patients with osteoarthritis also showed reduced PGC-1α mRNA and protein expression, supporting a role for muscular PGC-1α deficiency [75]. In the rabbit PTOA model, joint instability downregulated muscle PGC-1α while increasing Atrogin-1 and MuRF1 [75]. Exercise and joint distraction restored PGC-1α and suppressed atrophy markers, whereas ZLN005, a PGC-1α agonist, produced similar protective effects [75]. Table 1 summarizes PGC-1α dysregulation in musculoskeletal pain.

5.2. Peripheral Nerve Injury

Peripheral nerve injury models including chronic constriction injury (CCI), spinal nerve ligation (SNL), and spared nerve injury (SNI), consistently highlight the ability of PGC-1α to stimulate mitochondrial synthesis and abolish nerve injury-induced hypersensitivity [74,92]. However, the biological consequences of PGC-1α dysregulation differ across spinal neurons, microglia, dorsal root ganglion neurons, and immune cells within the injured peripheral nerve [21,23,41,71,74,77,95,96]. Therefore, mechanistic evidence for PGC-1α’s causal role in chronic pain should be considered as a strength of evidence.

In the spinal cord, PGC-1α appears to support mitochondrial biogenesis and redox homeostasis in nociception [92]. Sun et al. (2022) showed that mitochondrial biogenesis within spinal tissue is altered in association with CCI-driven neuropathic hypersensitivity [92]. Under this experimental design, application of the Nrf2 activator RTA-408 upregulated PGC-1α and mitigated mechanical hypersensitivity and thermal nociceptive responses [92]. The PGC-1α activator ZLN005 also produced significant analgesia. This effect, and that of RTA-408, was lost when PGC-1α was pharmacologically inhibited, supporting a causal role of PGC-1α in RTA-408-induced mitochondrial antinociception [92].

Heat shock protein 22 (HSP22) is involved in driving mitochondrial renewal and protects cells against oxidative damage and neuronal loss in brain disorders [97]. Notably, a marked reduction of HSP22 in spinal neurons has been linked to the progression of neuropathic pain behaviors [98]. Intrathecal recombinant HSP22 (rhHSP22) attenuated both mechanical hypersensitivity and thermal pain responses in SNI rat models [98]. In line with this evidence, rhHSP22 lowered ROS levels via the stimulation of spinal AMPK/PGC-1α signaling [98]. In addition, knocking down PGC-1α with siRNA eliminated the therapeutic pain relief conferred by rhHSP22 [98]. The findings provide causal evidence that PGC-1α is required for HSP22-mediated protection in neuropathic nociception [98].

PGC-1α also influences neuroimmune signaling in the spinal dorsal horn [21]. Chen et al. (2025) revealed that spinal PGC-1α activation alleviates CCI-induced neuropathic pain by interrupting a reciprocal cycle involving mitochondrial malfunction and NLRP3 inflammasome activation [21]. In the spinal dorsal horn, CCI increased pro-inflammatory CD68/IBA1 and decreased ARG1/IBA1 microglia while altering inflammatory cytokines [21]. PGC-1α activation restored mitochondrial homeostasis and suppressed NLRP3 inflammasome signaling to restrain microglial neuroinflammation in CCI [21]. Consistently, Zhou and colleagues showed that metformin increased PGC-1α signaling and reduced CD86, iNOS, TNF-α, and IL-1β as inflammatory macrophage markers [95]. Additionally, metformin enhanced nerve regeneration and remyelination by increasing NF200 and myelin basic protein [95].

Additional evidence supports a role for PGC-1α in spinal mitochondrial adaptation and neuroprotection [77]. The selective 5-HT_1F receptor agonist lasmiditan alleviated SNI-induced pain through PGC-1α-dependent induction of spinal mitochondrial biogenesis [77]. These observations are consistent with research by Simmons and co-workers, who demonstrated that administration of the selective 5-HT_1F receptor agonist LY344864 upregulated spinal cord PGC-1α mRNA levels and enhanced functional recovery following spinal cord injury [99]. This bioenergetic recovery suggests that 5-HT_1F receptor agonists exert neuroprotective effects by activating PGC-1α and attenuating nerve injury-induced pain [77,99]. ChREBP was also reported to promote PGC-1α transcription in spinal microglia, thereby suppressing neuroinflammation and neuronal hyperexcitability in neuropathic pain [96].

In the CNS, mitochondrial outer membrane translocator protein (TSPO) shows promise in alleviating neuropathic pain through regulating mitochondrial activity [100]. Ro5-4864, a TSPO agonist, relieved mechanical hypersensitivity by upregulating PGC-1α pathways, which optimized mitochondrial activity and reinforced antioxidant protection [100]. Consistent with these findings, Li et al. (2025) established that boosting TSPO levels mitigated SNI-driven neuropathic pain through restored mitochondrial function and reduced pyroptosis in dorsal horn neurons [101]. The pharmacological upregulation of TSPO activated PGC-1α and conferred antinociceptive actions [101]. However, blocking PGC-1α abolished the beneficial effects of TSPO on mitochondrial balance and pyroptosis, supporting a causal contribution of PGC-1α to TSPO-mediated antinociception [101].

Epigenetic mechanisms also contribute to neuropathic pain by repressing antinociceptive genes [23]. PGC-1α can be suppressed transcriptionally during neuropathic pain through DNA methylation, histone modification, and chromatin remodeling [102]. RNA-seq analysis identified Sp1 as related to CCI-provoked neuropathic pain and predicted its binding to the PGC-1α promoter [23]. Spinal Sp1 upregulation repressed PGC-1α expression by recruiting histone deacetylase 2 (HDAC2) to the PGC-1α promoter [23]. Silencing Sp1 reduced inflammation, mitigated mitochondrial dysfunction in the spinal cord, and improved pain sensitivity [23]. Likewise, overexpressing PGC-1α ameliorated CCI-provoked neuropathic pain and mitochondrial dysfunction [23]. This points to epigenetic regulators such as Sp1 or HDAC2 as potential targets to prevent PGC-1α silencing in chronic neuropathic pain [23].

Additional evidence indicates that stimulating G protein-coupled receptor 39 (GPR39) recruits PGC-1α to drive mitochondrial biogenesis and mitigate mechanical allodynia [74]. Dietary ketosis boosted spinal dorsal horn PGC-1α levels, thereby mitigating CCI-triggered mechanical and thermal hypersensitivity [103]. Melatonin inhibited SNL-induced neuropathic pain by enhancing PGC-1α expression and improving mitochondrial membrane potential in dorsal root ganglia [104]. Bioactive molecules in turmeric alleviate mechanical hypersensitivity by inhibiting glial activation and restoring mitochondrial function across both the spinal cord and amygdala [105].

In essence, across CCI, SNI, and SNL models, reduced PGC-1α is consistently associated with mitochondrial malfunction, oxidative damage, and persistent neuropathic pain behaviors [98,103,104]. The Sp1/HDAC2 provide epigenetic repression of PGC-1α, thereby promoting a pro-nociceptive state [23]. Activation of PGC-1α by Nrf2, TSPO, AMPK, 5-HT1F, GPR39, HSP22, ChREBP, metformin, melatonin, and turmeric restores mitochondrial biogenesis in pain models [77,92,96,98,100,104]. However, these interventions produce biological effects through various molecular targets [106,107,108]. Therefore, increased PGC-1α expression alone could not establish that PGC-1α mediates the antinociceptive effects. The stronger evidence supporting PGC-1α as a causal regulator of neuropathic pain comes from studies in which its manipulation changes mitochondrial function and pain behaviour using PGC-1α inhibition, knockdown, overexpression, or rescue approaches [23,98,101,109]. A summary of PGC-1α dysregulation in peripheral nerve injury is provided in Table 2.

5.3. Chemotherapy-Induced Neuropathic Pain

Paclitaxel-induced neuropathic pain (PINP) impaired mitochondrial biogenesis in the nociceptive system, with reduced levels of PGC-1α in the CNS [110]. In a rat model of PINP, formoterol enhanced PGC-1α expression and blocked mechanical allodynia [110]. This is an indication that the β2-adrenergic system can relieve chemotherapy-induced neuropathic pain by inducing PGC-1α-dependent mitochondrial renewal [110]. Recently, Mo and colleagues (2026) documented that pituitary adenylate cyclase-activating polypeptide (PACAP) relieved PINP by activating neuronal PGC-1α [80]. PACAP upregulated PGC-1α and reduced oxidative damage, accompanied by a reduction in mechanical allodynia and hyperalgesia [80]. Pharmacological inhibition of PGC-1α abolished these effects, suggesting that PACAP alleviates neuropathic pain through regulation of mitochondrial health [80].

5.4. Cancer-Induced Bone Pain

In a rodent model of cancer-provoked bone pain, Ge et al. (2022) indicated polarization of spinal microglia alongside suppressed PGC-1α and reduced glutathione peroxidase 4 (GPx4) [85]. Intraperitoneal naringenin administration relieved bone cancer-induced mechanical allodynia and promoted spinal GPx4 expression via the AMPK/PGC-1α system [85]. Chen et al. (2025) support this mechanism by showing that spinal PGC-1α activation abolished neuropathic pain by reprogramming microglia [21]. Impressively, reduced PGC-1α expression was observed in spinal GABAergic interneurons [86]. Treatment with the intrathecally administered PGC-1α agonist ZLN005 preserved GABAergic interneuron populations by alleviating mechanical allodynia and restoring mitochondrial biogenesis [86]. These biological effects were reversed by the PGC-1α antagonist SR-18292, indicating that PGC-1α-dependent mitochondrial protection in inhibitory interneurons plays a role in limiting cancer-induced bone pain [86].

5.5. Diabetic-Induced Neuropathic Pain

Diabetic nerve injury is marked by oxidative stress and impairment in PGC-1α-dependent mitochondrial biogenesis. In painful diabetic neuropathy, suppression of this pathway is linked to mitochondrial abnormality and peripheral nerve damage, particularly in Schwann cells and sciatic nerve tissue [81,82,83,84]. Notably, neuroprotective compounds such as quercetin, honokiol, mitochondria-derived peptide, and Tang Bi formula have been shown to counteract these pathological changes by reactivating AMPK/PGC-1α-dependent mitochondrial biogenesis [81,82,83,84]. These studies support PGC-1α as a metabolic target through which potential neuroprotective agents could preserve mitochondrial integrity, improve redox balance, and attenuate nerve injury in diabetic neuropathy [81,82,83,84]. Table 3 summarizes evidence of PGC-1α dysregulation in chemotherapy-induced neuropathic pain, cancer-induced bone pain, and diabetic-induced neuropathic pain.

5.6. Fibromyalgia

Mitochondrial dysfunction in skeletal muscle and hippocampus is coupled to suppression of PGC-1α signaling in fibromyalgia models [76,87,88]. This suppression promotes redox imbalance and mitochondrial abnormalities, which contribute to nociplastic pain and cognitive impairment [76,87,88]. Belviranlı and colleagues reported that exercise training and coenzyme Q10 improve fibromyalgia symptoms [87,88]. These benefits resulted from the stimulation of hippocampal PGC-1α, which improved redox homeostasis and mitochondrial renewal in skeletal muscle fibers [87,88]. Similarly, melatonin restored PGC-1α signaling, mitigated neuronal sensitization, and suppressed neuroinflammation [76,111]. Such evidence highlights that PGC-1α serves as a neuroprotective target mediating the beneficial effects of both pharmacological and non-pharmacological measures, including exercise, coenzyme Q10, and melatonin, in fibromyalgia [76,87,88,111]. A summary of PGC-1α dysregulation in fibromyalgia is provided in Table 4.

5.7. Chronic Headache Disorders

Chronic headache disorders, particularly migraine are associated with mitochondrial malfunction and alteration in PGC-1α-related signaling in trigeminal pathways [73,89]. Prior findings using nitroglycerin-triggered migraine models show that lower PGC-1α levels correlate with central sensitization and inflammatory pathways in chronic migraine progression [73]. Guan and collaborators demonstrated that mitochondrial dysregulation in the trigeminal ganglion promotes nociception in nitroglycerin-triggered migraine by impairing PGC-1α and mitochondrial health [89]. Similarly, administration of the mitochondrial-targeted peptide SS-31 alleviated pain responses and revived mitochondrial activity by boosting PGC-1α in an inflammatory soup model [90]. Table 5 summarizes PGC-1α dysregulation in chronic headache disorders.

5.8. Opioid-Induced Hyperalgesia

Chronic opioid exposure is associated with opioid-induced hyperalgesia and tolerance through downregulation of PGC-1α-dependent mitochondrial signaling [26,91]. Jie et al. (2025) showed that morphine tolerance is correlated to enhanced CCL2 and inhibition of Nrf2/PGC-1α signaling [91]. These changes promote oxidative stress and neuronal apoptosis, thereby reducing analgesic efficacy [91]. In this study, pharmacological manipulation with the CCL2 inhibitor Bindarit or the PGC-1α agonist ZLN005 abolished spinal apoptosis and reversed tolerance from morphine administration [91]. Feng et al. (2025) reported a similar pattern in remifentanil-induced hyperalgesia, where activation of spinal p38 MAPK suppressed PGC-1α, promoted neuronal ROS release, thereby contributing to pain hypersensitivity [112]. In line with these results, Kashiwagi et al. (2021) showed that recombinant PGC-1α reduced mitochondrial superoxide and attenuated spinal morphine tolerance [26]. Interestingly, NeuroAid improved morphine-induced cognitive deficits, potentially by upregulating PGC-1α [113]. The basolateral amygdala SIRT1/PGC-1α pathway and mitochondrial dysregulation were also implicated in morphine withdrawal symptoms [114]. Table 6 summarizes PGC-1α dysregulation in opioid-induced hyperalgesia.

6. Opportunities in Targeting PGC-1α for Chronic Pain

PGC-1α represents a potential neurotherapeutic target in chronic pain due to its involvement in regulating mitochondrial health, antioxidant defense, and neuroinflammation [95,97]. In both chronic pain models and neurodegenerative or neurological conditions, declining expression of PGC-1α plays a key role in neuropathological alterations [63,97]. However, most available evidence is derived from preclinical brain and spinal cord samples, dorsal root ganglia, hippocampus or injured peripheral nerves, which are not readily accessible for assessment in patients [26,84,91,110,115,116]. Skeletal muscle could provide an accessible tissue source for evaluating PGC-1 in conditions involving muscle dysfunction such as osteoarthritis and fibromyalgia [75,111,117]. However, it remains unclear whether skeletal-muscle PGC-1α signaling reflects PGC-1α activity within central pain pathways.

Bioactive molecules, including resveratrol, berberine, quercetin, evodiamine, and salvianolic acid A, have been reported to confer neuroprotection by increasing PGC-1α levels and improving mitochondrial resilience in preclinical pain models [84,118,119,120,121]. Other phytochemicals, including magnolol and polyphenols, were also explored for PGC-1α-targeting activity [39,122]. These compounds have been linked to mitochondrial protection and reduced oxidative stress, supporting their potential relevance for PGC-1α-mediated modulation of pain pathways [105,119,121,122]. In addition, compounds such as mitoquinone, pyrroloquinoline quinone, alpha-lipoic acid, acetyl-L-carnitine, and nicotinamide riboside are promising mitochondrial protectants and antioxidants for further study of PGC-1α in chronic nociception [93,123,124,125].

Small-molecule PGC-1α activators and stabilizers such as ZLN005 and other high-throughput screening hits may offer an additional strategy for chronic pain by enhancing PGC-1α expression and mitochondrial biogenesis [27,126]. Neuroprotective agents such as N-acetylcysteine and idebenone may also act as antioxidants, mitochondrial protectants, or neuroinflammation modulators [127,128]. These compounds warrant further investigation for their potential roles in modulating PGC-1α in pain mechanisms.

An additional translational opportunity is that PGC-1α-targeted approaches could serve as an opioid-sparing add-on to opioid analgesics. This is evident by the fact that spinal PGC-1α was downregulated during morphine tolerance, whereas restoration of PGC-1α attenuated mechanical and thermal hypersensitivity in morphine-tolerant rodents [26]. Recent studies implicate PGC-1α/SIRT3 and Nrf2/PGC-1α impairment in remifentanil-induced hyperalgesia and morphine tolerance, respectively, both of which are reversed by ZLN005 intervention [91,112]. These identify PGC-1α activation as a candidate strategy to abolish opioid-induced tolerance and hyperalgesia [91,112]. Chronic pain management sometimes requires combination therapy to improve efficacy and limit opioid adverse effects [129]. Future studies should test whether PGC-1α activators can reduce opioid dose requirements or enhance the therapeutic efficacy of opioids. Direct comparisons of PGC-1α activators with opioid analgesics are also required to evaluate their potential as standalone non-opioid options.

7. Challenges and Limitations in Targeting PGC-1α for Chronic Pain

Despite its compelling role in mitochondrial function and pain modulation, targeting PGC-1α for chronic pain presents several biological, pharmacological, and translational limitations. A major translational challenge in targeting PGC-1α includes the need for tissue-specific modulation to avoid systemic effects, given its highly inducible regulation of mitochondrial and inflammatory pathways [63,65,130,131,132]. For instance, PGC-1α overexpression improves cardiac function in young wild-type rodents but accelerates ageing in older mice [133]. Similarly, PGC-1α supports metabolic homeostasis at physiological levels, but excessive expression may promote insulin resistance [134,135].

Sex differences can complicate PGC-1α targeting because males and females respond differently [136]. For example, exercise-induced PGC-1α expression appears to be sex-dependent. Besides, cardiac studies suggest that PGC-1α contributes to sex-specific variation in cardiac function and cardiovascular risk [136]. Recent studies also show that PGC-1α-dependent thermogenesis in brown adipose tissue is influenced by sex [137]. This is concerning because chronic pain, including fibromyalgia and migraine, is more common in females [138,139]. Specifically, sex representation varied across fibromyalgia models, with several reserpine-induced studies using female Wistar rats [76,87,115], while another study used male Sprague-Dawley rats [111]. In contrast, studies of nitroglycerin-induced migraine used male mice [73,89], whereas the inflammatory-soup headache study was predominantly male, with limited female inclusion [90]. Therefore, Such data reinforce the need to consider sex as a biological variable when interpreting PGC-1α findings from experimental models [136,137]. Given that PGC-1α is sex-dependent, this gap warrants direct attention.

Natural molecules such as curcumin and berberine have shown neuroprotective effects in preclinical studies by targeting PGC-1α [28,140,141]. However, these molecules influence other signaling pathways, including AMPK and Nrf2 [63]. Therefore, their effects may not be attributable solely to direct PGC-1α activation [142]. Clinically used compounds such as melatonin and metformin appear promising for PGC-1α-centered therapy [76,143]. However, more studies are required to define the optimal dosing and translational potential of metformin-melatonin combinations in pain models [144]. In addition, the small-molecule PGC-1α agonist ZLN005 has shown activity in mouse models, whereas SR-18292 has been documented to inhibit PGC-1α activity in animal studies [68]. However, variations in chronic pain models and the species gap between rodents and humans remain major barriers to clinical translation [145]. Finally, PGC-1α serves as a regulator of gene expression, coactivating transcription factors rather than a classic receptor, making direct pharmacological targeting particularly challenging [131]. Future research should consider modulating PGC-1α through post-translational protein modifications alongside interactions with target proteins to influence its stability and activity [20,27,131]. Furthermore, structural biology could potentially identify functional domains of PGC-1α for future structure-based drug design. These limitations highlight that substantial future research is required to translate PGC-1α modulation into safe, effective, and sex-specific clinical therapies for chronic pain.

8. Conclusions and Future Directions

PGC-1α appears to be a promising disease-modifying neuroprotective target in chronic pain by modulating mitochondrial dysfunction, oxidative stress, and neuroinflammation. However, its effects may vary across tissues and pain conditions. Natural compounds including resveratrol, berberine, quercetin, evodiamine, and salvianolic acid A, some clinically used drugs, and small-molecule modulators show potential as PGC-1α-targeting analgesic agents. However, most findings remain preclinical, with challenges related to sex specificity, tissue specificity, and limited translation to humans. Future scientific work should define the role of PGC-1α in sex-specific pain model and optimize dosing to develop more selective, effective, and tolerable analgesics.

The development of lipid nanoparticles or blood-brain-barrier penetrating formulations will be important for directing PGC-1α activators to the CNS. This is because targeted delivery systems could help reduce systemic side effects by limiting off-target exposure and improving CNS delivery. Future preclinical work should determine which types of chronic pain benefit most from PGC-1α modulation. Combining PGC-1α modulators with low-dose opioids may reduce tolerance, as PGC-1α stimulation has been demonstrated to mitigate both morphine tolerance and chronic pain. In addition, future studies should investigate whether PGC-1α upregulation can also mitigate other major opioid-related adverse effects, such as respiratory depression, gastrointestinal dysmotility, and physical dependence or withdrawal syndromes.

Authors’ Contribution: MHA: Conceptualization, Investigation, Writing - original draft, Writing – review & editing, Formal analysis, Data curation. KGM: Writing – review & editing, Methodology, Formal analysis, Visualization. YA: Writing – review & editing, Methodology, Visualization. MM: Writing – review & editing, Formal analysis, Visualization. AIJ: Writing – review & editing, Supervision, Project administration, Data curation. IY: Writing – review & editing, Formal analysis, Supervision, Project administration, Validation. All the authors read and approved the final manuscript.